UC San Diego

Desmoplakin (DSP) is a critical protein component of desmosomes, specialized cell structures that function as intercellular junctions and are essential for maintaining the structural integrity of cardiac muscle cells. Mutations or loss of DSP are linked to arrhythmogenic right ventricular cardiomyopathy (ARVC), a genetic cardiac disease characterized by ventricular arrhythmias, fibrofatty myocardial replacement, and sudden cardiac death. ARVC patients with DSP mutations often show a unique form of cardiomyopathy associated with myocarditis, further complicating the clinical presentation of this disease. In my studies, I have investigated the therapeutic potential of restoring Connexin-43 (Cx-43), a key gap junction protein, through gene therapy in a novel mouse model of myocarditis-driven DSP cardiomyopathy. Utilizing a cardiac-specific DSP heterozygous mice (DSP Het) invoked with inflammatory stress, I have assessed the effects of adeno-associated virus (AAV9) mediated Cx-43 gene therapy on electrical, structural and cardiac function. I hypothesized that restoring Cx-43 levels will reduce myocardial inflammation indirectly by stabilizing DSP levels, delaying the progression of ARVC, and improving the electrical and mechanical integrity of the heart. My thesis studies have shown that Cx-43 restoration stabilizes electrical, mechanical, and structural function of the heart, and improves the levels of desmosomal proteins, particularly DSP. Electrocardiogram (ECG) and magnetic resonance imaging (MRI) analyses showed notable improvements in electrical conduction and cardiac function, respectively, in the treated compared untreated (diseased) group. Histological examinations revealed that treated mice showed no signs of fat or fibrosis, indicating a structural improvement. In conclusion, these findings suggest that Cx-43 gene therapy mitigates the adverse effects of inflammatory mediated DSP deficiency, providing a promising therapeutic strategy for myocarditis driven ARVC in patients with DSP mutations. This research advances our understanding of the molecular mechanisms linking DSP deficiency to myocarditis, highlighting the potential for developing targeted therapies for ARVC patients with DSP mutation.